The enzyme, p70S6 kinase (also known as p70S6K, p70S6K1, pS6K, S6K, S6K1) is a serine-threonine kinase and a member of the AGC family. It is a downstream effector of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway and p70S6K undergoes phosphorylation and activation in response to growth factors such as IGF-I, EGF, TGF-[alpha] and HGF.
Activation of p70S6K in turn phosphorylates a number of proteins involved in protein translation including Ribosomal protein S6 (RPS6), eIF4B and eEF2K. The net effect of this is to promote translation leading to an increase in protein synthesis in a cell. High levels of protein synthesis are required for cellular proliferation. It has also been shown that p70S6K has a necessary role in the mitotic cycle of a cell (Lane et al, Nature, 1993, 363(6425):170-2).
The kinase p70S6K has been shown to be constitutively activated in human tumour cells, leading to tumour cell proliferation. Inhibition of the mTOR/p70S6K pathway has been shown to lead to a decrease in tumour cell proliferation and an increase in tumour cell apoptosis (Pene et al (2002) Oncogene 21, 6587 and Le et al (2003) Oncogene 22, 484). Inhibition of p70S6K activity would therefore present an attractive approach for the treatment of cancer.
The mTOR/p70S6K pathway has been shown to be activated in renal cell carcinoma and is inhibited by CCI-779 (Robb, V. A.; Karbowniczek, M.; Klein-Szanto, A. J.; Henske, E. P. J Urol 2007, 177, 346-52). Furthermore, patients with glioblastoma multiforme whose tumours express high levels of phosphorylated p70S6K have been found to benefit from treatment with CCI-779 (Galanis et al. J. Clin. Oncol. 2005, 23, 5294-304).
In addition, a significant linear association between time to disease progression and inhibition of p70S6K activity in peripheral blood mononuclear cells (PBMCs) following administration of the mTOR inhibitor CCI-779 has been reported for Renal Cell Carcinoma patients by Peralba et al [(2003) Clinical Cancer Research 9, 2887]. This indicates that activity of p70S6K is a driver of disease in this setting and that p70S6K activity can be potentially be used as a clinical biomarker.
The gene RPS6KB1 that codes for p70S6K, is localized to chromosomal region 17q23 and this region is amplified in Breast Cancer (Cancer Res. (1999) 59: 1408-11 Localization of pS6K to Chromosomal Region 17q23 and Determination of Its Amplification in Breast Cancer). This leads to over-expression of p70S6K protein and a statistically significant association between amplification and poor prognosis has been observed in breast cancer patients (Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J. Natl. Cancer Inst. 2000; 92:1252-9).
Furthermore, Belletti et al published that S6K1 mediates survival and recurrence of Breast Cancer following surgery (Mol Oncol. 2014 May; 8(3):766-80).
P70S6K has a role in migration and invasion of ovarian cancer (p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells, Oncogene (2011), 1-13). In addition, it has been revealed that p70S6K has a role in promoting invasion, migration and metastasis of highly aggressive Triple-Negative Breast Cancer cells (Targeting p70S6K Prevented Lung Metastasis in a Breast Cancer Xenograft Model, Akar et al, Molecular Cancer Therapeutics (2010), 9 (5), 1180 and Hung et al, S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer, Am. J. Transl, Res. 2014 Jul. 18; 6(4):361-76).
In addition, Lymphangioleiomyomatosis (LAM) is a disease typified by hyper-activation of the PI3K/Akt/mTOR/p70S6K axis due to mutation inactivation of the repressor complex, Tuberous Sclerosis Complex (TSC). LAM cells are also metastatic, giving rise to metastasis in the lung.
LAM is a rare destructive lung disease, almost exclusively of women, and is associated with the metastasis of tuberin-null cells (Taveira-DaSilva et al. (2006). Cancer Control. 2006; 13:276-285). Metastatic lesions develop in distant organs including lungs, kidney and lymph nodes, representing a severe and debilitating disease burden.
LAM occurs either sporadically or as a manifestation of Tuberous Sclerosis Complex (TSC), a dominant autosomal inherited disorder (Expert review on http://www.orpha.net). LAM and TSC disorders are characterized by nullifying mutations in tumour suppressors TSC1 or TSC2 leading to hyper activation of mTOR and of S6K1. This in turn drives cell growth & proliferation of LAM cells (Holz et al. (2014), Cell Cycle 2014; 13:371-382). S6K1 is also known to promote metastasis in other cancers: breast (Akar et al. (2010), Mol Cancer Ther; 9(5)) and ovarian (Wong et al. (2011), Oncogene (2011) 30, 2420-2432). Due to the reliance of LAM cells on S6K1, and of the likely role of S6K1 in the metastatic process, it is anticipated that an S6K1 inhibitor will have disease-modifying properties for LAM.
Sporadic LAM has a prevalence of approximately 1 in 125,000 births whereas Pulmonary LAM, arising from TSC, has a prevalence of approximately 1 in 15,000 births (figures from internet rare disease database, http://www.orpha.net). No approved therapies exist for LAM and hence LAM is currently classified as an orphan disease.
Given that p70S6K promotes translation, it is known that p70S6K has a crucial role in the pathology of diseases that rely on excessive protein synthesis (for example, Fragile X Syndrome, Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice. Klann et al, Neuron, Volume 76, Issue 2, p325-337, 18 Oct. 2012). Furthermore, p70S6K has a role in the pathology of cancers involving synthesis of oncogenic proteins such as c-Myc e.g. pancreatic cancer (The mTORC1/S6K1 Pathway Regulates Glutamine Metabolism through the eIF4B Dependent Control of c-Myc Translation, Blenis et al, Current Biology, Volume 24, Issue 19, p2274-2280, 6 Oct. 2014). For treatment of these conditions it would be advantageous to use an orally bioavailable p70S6K inhibitor to correct the excessive protein synthesis.
P70S6K has been implicated in the pathology of a number of cancers of the brain. Such conditions include, but are not limited to:                Brain metastases arising from cancers elsewhere in the body, for example brain metastases arising from a breast cancer such as Triple-Negative Breast Cancer (Distant metastasis in triple-negative breast cancer. Neoplasma 2013; 60: 290-294)        Brain metastases from metastatic breast cancer (Central nervous system or brain metastases traditionally occur in 10-16% of metastatic breast cancer patients and are associated with a dismal prognosis—see Breast Dis. 2006-2007; 26:139-47.)        Gliomas and Glioblastomas (S6K1 Plays a Key Role in Glial Transformation, Cancer Research (2008), 68(16), 6516-6523)        
Furthermore, a p70S6K inhibitor may be particularly useful for treating the following cancers which are reliant on p70S6K signalling:                Bladder cancer        Breast cancer        Colo-rectal cancer (CRC)        Diffuse large B-cell lymphomas (DLBCL)        Gallbladder cancer        Gliomas and Glioblastomas        Head and Neck cancers        Hepatocellular carcinoma        Human Olfactory Neuroblastoma        Leukaemias        Lymphomas        Nasopharyngeal carcinoma        Neuroendocrine cancer        Non-Small Cell Lung Cancer (NSCLC)        Small cell lung cancer        Ovarian cancer        Pancreatic cancer        Pheochromocytoma        Renal Cell Carcinoma (RCC)        Squamous cell carcinoma        Metastases, for example bone metastases and lung metastases        
P70S6K also has a crucial role in the pathology of a number of neurodevelopmental diseases (many referenced in The Autistic Neuron: Troubled Translation?. Bear et al, Cell 135, Oct. 31, 2008). In particular, these diseases are caused by the excessive protein synthesis that is driven by P70S6K. Such conditions include, but are not limited to:                Fragile X Syndrome, a rare neuro-developmental disease caused by excessive levels of p70S6K activity        Autism and Autism Spectrum Disorders        Fragile X-associated tremor/ataxia syndrome (FXTAS)        Angleman's syndrome        Tuberous sclerosis        PTEN hamartoma syndrome        MECP2 duplication syndrome        Neurofibromatosis        Alzheimer's Disease (refer to (1) Oddo et al, Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease, The Journal of Neuroscience, Oct. 14, 2015, 35(41):14042-14056 and (2) Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature, Journal of Neuroscience (2014), 34(23), 7988-7998)        Down Syndrome (mTOR Hyperactivation in Down Syndrome Hippocampus Appears Early During Development, Journal of Neuropathology & Experimental Neurology (2014), 73(7), 671-683)PTEN Hamartoma Syndrome        
PTEN hamartoma tumour syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumour suppressor PTEN. These allelic disorders, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are associated with unregulated cellular proliferation leading to the formation of hamartomas (benign and malignant tumours of the thyroid, breast, and endometrium) (Genetics in Medicine (2009) 11, 687-694). The absence of PTEN leads to loss of down-regulation of phosphorylated Akt which in turn allows for unchecked survival, growth and proliferation of the cells in question. As S6K1 is a key effector of Akt, an S6K1 inhibitor may have utility in controlling the growth of the cancer. Prevalence of PHTS is currently unknown.
Neurofibromatosis Type 1
Neurofibromatosis type 1 is a condition characterized by changes in skin colouring (pigmentation) and the growth of tumours along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people. Most adults with neurofibromatosis type 1 develop neurofibromas, which are noncancerous (benign) tumours that are usually located on or just under the skin. These tumours may also occur in nerves near the spinal cord or along nerves elsewhere in the body. Some people with neurofibromatosis type 1 develop cancerous tumours that grow along nerves. These tumours, which usually develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumours. People with neurofibromatosis type 1 also have an increased risk of developing other cancers, including brain tumours and cancer of blood-forming tissue (leukaemia).
Neurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people worldwide and currently surgery is the main treatment option; it is classed as an orphan disease as no targeted therapies exist (http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1)
Mutations in the NF1 gene cause neurofibromatosis type 1. The NF1 gene provides instructions for making neurofibromin protein. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumour suppressor. Mutations in the NF1 gene lead to the production of a non-functional version of neurofibromin that cannot regulate cell growth and division. As a result, tumours such as neurofibromas can form along nerves throughout the body. An S6K1 inhibitor may control growth of cells expressing mutated NF1 gene by dampening production of neurofibromin protein and other proteins essential to growth of the tumour.
Role of P70S6 in Neurological Diseases
P70S6K also has a crucial role in the pathology of a number of neurodevelopmental diseases (many referenced in The Autistic Neuron: Troubled Translation?. Bear et al, Cell 135, Oct. 31, 2008). In particular, these diseases are caused by the excessive protein synthesis that is driven by P70S6K.
It is well known that precise translation control (protein synthesis) is absolutely required for neurological processes of the brain such as long-lasting synaptic plasticity and the formation of long-term memory. Moreover, alterations in translational control are a common pathophysiological feature of human neurological disorders, including developmental disorders, neuropsychiatric disorders, and neurodegenerative diseases.
Furthermore, it is known that translational control mechanisms are susceptible to modification by small molecules that penetrate the brain (Klann and Santini, Dysregulated mTORC1-dependent translational control: from brain disorders to psychoactive drugs, Front. Behav. Neurosci., 8 Nov. 2011, doi: 10.3389/fnbeh.2011.00076).
S6K1 is well known as a master regulator of protein biosynthesis via its role in translation initiation as well as phosphorylation and activation of various substrates that drive protein production (eIF4B, PDCD4, SKAR, eEF2K, RPS6—for review refer to Ma and Blenis, Nature Reviews Molecular Cell Biology 10, 307-318 (May 2009), doi:10.1038/nrm2672).
The following disorders are typified by underlying aberrations in regulation of protein translation which is linked to the pathologies observed. An S6K1 inhibitor, which acts by reducing excessive protein translation may therefore have utility as a therapy in such disorders.
It is possible to classify certain disorders into sub-groups: (1) Neurodevelopmental Disorders (2) Neurodegenerative Diseases. Within each sub-class the disorders are linked by common themes:
1. Neurodevelopmental Disorders
Neurodevelopmental disorders are defined as diseases caused by abnormal development of the brain during the first two decades of life. It is possible to define a subgroup of these disorders that are characterized by single-gene mutations. A common molecular abnormality in several of these disorders is loss-of-function mutations and/or deletion of genes that encode proteins that normally repress the mTORC1 signalling pathway. These disorders are listed below.
Fragile X Syndrome
Fragile X syndrome (FXS) is a genetic condition that gives rise to a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females, owing to the fact that the condition is inherited via the X-chromosome. Affected individuals usually have delayed development of speech and language by age 2. Most males with FXS have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with FXS may also have anxiety and hyperactive behaviour such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks.
About one-third of individuals with FXS have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with FXS. Most males and about half of females with FXS have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macro-orchidism) after puberty. FXS occurs in approximately 1 in 4,000 males and 1 in 8,000 females.
Mutations in the Fmr1 gene cause FXS. The Fmr1 gene provides instructions for making a protein called fragile X mental retardation 1 protein, or FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses.
Nearly all cases of FXS are caused by a mutation in a DNA segment, known as the CGG triplet repeat, in the Fmr1 gene. Normally, this DNA segment is repeated in the range between 5 and 44 times (more commonly either 29 or 30 times). In people with FXS, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the Fmr1 gene, which prevents the gene from producing FMRP.
FMRP is a repressor of protein translation. In the case of FXS patients, who either experience a loss or shortage of FMRP, there is no repression of translation, leading to excessive production of an array of proteins normally controlled by FMRP. A number of these proteins are expressed in the neurons and control synaptic plasticity (memory formation, learning, ability to store information). Lack of control of production of these proteins leads to the neuropathological state observed in FXS patients. Klann et al published that S6K1 has a central role in the excessive translation of these proteins and that genetic knock-out of S6K1 resulted in correction of phenotypes in the mouse model of FXS (Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice. Neuron 76, 325-337, 2012). It has been determined that S6K1 inhibitors described herein also have the ability to dampen protein synthesis in the neurons, leading to correction of aberrant phenotypes in a mouse model of FXS.
Furthermore, Tassone et al (Genes, Brain and Behavior (2012), doi: 10.1111/j.1601-183X.2012.00768.x) published that lymphocytes isolated from the blood of human FXS patients exhibited higher levels of phosphorylated (activated) p70S6K and also higher levels of phosphorylated RPS6, the direct substrate of S6K1. This confirms that p70S6K is more highly activated in human FXS patients and supports the notion of inhibiting p70S6K activity in order to correct the disease. In addition, this represents a possible clinical biomarker so as to assess the pharmacodynamics effect of the p70S6K inhibitor in the clinic.
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia. It is an X-linked genetic disorder and as such, the disease primarily affects males (Orphanet rare disease database, http://www.orpha.net/consor/cgi-bin/index.php?lng=EN)
Prevalence is estimated at 1-9 in 100,000 individuals. The age of onset of tremor and/or ataxia in males is about 60 years. The clinical presentation is variable with dominant manifestations including: intention tremor, progressive cerebellar gait ataxia, frontal executive dysfunction, cognitive decline, peripheral neuropathy, and dysautonomia. Other signs include mild Parkinsonism and psychiatric manifestations (depression, anxiety and agitation) with possible progression to dementia. Carrier females generally have less severe manifestations than males but also have an increased risk of primary ovarian insufficiency, chronic muscle pain, and hypothyroidism. FXTAS is caused by a CGG trinucleotide repeat expansion (55-200 repeats) in the permutation range of the Fmr1 gene. There is no specific treatment for FXTAS that targets the underlying pathological mechanism; FXTAS is therefore classed as an orphan disease. The CGG trinucleotide repeat expansion often leads to reduced levels of FMRP protein, a repressor of protein translation. This leads to excessive protein translation which may be counter-acted by use of an S6K1 inhibitor.
Autism and Autism Spectrum Disorders
Autism spectrum disorder (ASD) and autism are terms for a group of complex disorders of brain development. The disorders are characterized by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviours. A publication in 2013 titled the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) brought together all autism disorders into one umbrella diagnosis of ASD. Previously, they were recognized as distinct subtypes, including autistic disorder, childhood disintegrative disorder, pervasive developmental disorder—not otherwise specified (PDD-NOS) and Asperger syndrome. The U.S. Centers for Disease Control and Prevention (CDC) identify around 1 in 68 American children as on the autism spectrum. Studies also show that autism is four to five times more common among boys than girls. An estimated 1 out of 42 boys and 1 in 189 girls are diagnosed with autism in the United States. Overall, ASD affects over 3 million individuals in the U.S. and tens of millions worldwide (Autism Speaks website, http://www.autismspeaks.org/). Moreover, government autism statistics suggest that prevalence rates are on the increase. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the most common known cause of autism worldwide (Penagarikano et al (2007). The pathophysiology of Fragile X Syndrome. Annu. Rev. Genomics Hum. Genet. 8, 109-129). This causative link between FXS and autism indicates that an S6K1 inhibitor that exhibits efficacy in treating FXS may also be useful in treatment of autism and ASDs.
Angelman Syndrome
Angelman syndrome (AS) is a neurogenetic disorder that is usually diagnosed in infants and is characterized by developmental delay, severe intellectual disability, absent speech, exuberant behaviour with happy demeanor, motor impairment, and epilepsy. AS is caused by deficient UBE3A gene expression that may be caused by various abnormalities of chromosome 15 (Dan, B., Angelman syndrome: Current understanding and research prospects. Epilepsia, 2009. 50(11): p. 2331-2339). Although not precisely known, prevalence of AS among children and young adults is between 1/10,000 and 1/20,000 defining AS as a rare disease. Mutations in the E3 ubiquitin ligase UBE3A have been identified in AS, suggesting that ubiquitin-dependent protein turnover may be impaired in this disorder, possibly leading to elevated synaptic protein levels (Jiang and Beaudet, 2004). Furthermore, it has been disclosed that S6K1 inhibition can improve hippocampal synaptic plasticity and learning in a mouse model of Angelman syndrome (Cellular and Molecular Life Sciences pp 1-12). An S6K1 kinase inhibitor would exert its effect by reducing translation of synaptic protein levels.
Tuberous Sclerosis Complex
Tuberous sclerosis complex is a genetic disorder characterized by the growth of numerous noncancerous (benign) tumours in many parts of the body. These tumours can occur in the skin, brain, kidneys, and other organs, in some cases leading to significant health problems. Tuberous sclerosis complex also causes developmental problems, and the signs and symptoms of the condition vary from person to person.
Tuberous sclerosis complex often affects the brain, causing seizures, behavioural problems such as hyperactivity and aggression, and intellectual disability or learning problems. Some affected children have the characteristic features of autism, a developmental disorder that affects communication and social interaction, as described above. Benign brain tumours can also develop in people with tuberous sclerosis complex; these tumours can cause serious or life-threatening complications. Tuberous sclerosis complex affects about 1 in 6,000 people (http://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex)
Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex. The TSC1 and TSC2 genes provide instructions for making the proteins hamartin and tuberin, respectively. These proteins are involved in the signalling network of the PI3K pathway and act as tumour suppressors, inhibiting the activation of mTOR via Rheb-GTP. When TSC1 or TSC2 are mutated this leads to loss of tumour suppressor function, leading to mTOR hyper-activation.
Importantly, the mTORC1 inhibitor rapamycin has been shown to be effective in ameliorating learning and memory deficits in TSC2 heterozygous knockout mice (Ehninger et al., 2008b), suggesting that uncontrolled mTORC1 signalling is a core molecular mechanism involved in the behavioural abnormalities.
One of the functional effectors of mTOR is S6K1; therefore, inhibiting S6K1 function may have ameliorative effects in the disease
MECP2 Duplication Syndrome
MECP2 duplication syndrome is a genetic condition that is inherited in an X-linked pattern and occurs almost exclusively in males. It is characterized by moderate to severe intellectual disability. Most people with this condition also have weak muscle tone in infancy, feeding difficulties, poor or absent speech, and seizures that may not improve with treatment or muscle stiffness (spasticity). Individuals with MECP2 duplication syndrome have delayed development of motor skills such as sitting and walking. Many individuals with MECP2 duplication syndrome have recurrent respiratory tract infections. These respiratory infections are a major cause of death in affected individuals, with almost half succumbing by age 25. The prevalence of MECP2 duplication syndrome is unknown; approximately 120 affected individuals have been reported in the scientific literature. MECP2 duplication syndrome arises due to a duplication of the MECP2 gene which leads to excessive production of MeCP2 protein in the brain. MeCP2 is a regulator of expression of other genes. Whilst MeCP2 is critical for normal brain function, an excess can lead to abnormal regulation of the target genes (http://ghr.nlm.nih.gov/condition/mecp2-duplication-syndrome). An S6K1 inhibitor may reduce production of MeCP2 protein via global dampening of translation and may have utility as therapeutic intervention in this disease.
Down Syndrome
Down syndrome (DS) or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21 (Patterson, D (July 2009). “Molecular genetic analysis of Down syndrome.” Human Genetics 126 (1): 195-214). It is typically associated with physical growth delays, characteristic facial features, and mild to moderate intellectual disability. DS is the most common chromosome abnormality in humans, occurring in about one per 1000 babies born each year (Weijerman, M E; de Winter, J P (December 2010). “Clinical practice. The care of children with Down syndrome”. European journal of pediatrics 169 (12): 1445-52).
Recent publications have identified that mTOR hyper-activation plays a role in DS in the early stages of development. In control (non-DS) hippocampi phosphorylated S6 was only detected prenatally; it became undetectable 2 months postnatally. Conversely, for DS patients, phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. This was linked to increased expression of phosphorylated S6 protein (RPS6), phosphorylated p70S6K, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR in DS hippocampus compared with controls (J Neuropathol Exp Neurol. 2014 July; 73(7):671-83). Furthermore, it has been suggested that mTOR inhibitors such as Rapamycin or other Rapalogs may be of utility in treating Cognitive Deficits associated with DS (CNS Neurol Disord Drug Targets. 2014 February; 13(1):34-40). As S6K1 controls phosphorylation and activation of S6 protein, an S6K1 inhibitor may be of therapeutic utility in counteracting the hyper-activated mTOR signalling in DS patients.
2. Neurodegenerative Diseases
Alzheimer's Disease
The clinical symptoms of Alzheimer's disease (AD) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. AD accounts for 60% to 70% of cases of dementia (Burns, A; Lliffe, S (5 Feb. 2009). “Alzheimer's disease.” BMJ (Clinical research ed.) 338: b158). It is a devastating and relatively widespread disease—as of 2010, there were between 21 and 35 million people worldwide with AD (“Survival in dementia and predictors of mortality: a review”. International journal of geriatric psychiatry 28 (11): 1109-24).
At the molecular level, AD is associated with (1) the progressive accumulation of amyloid β-peptides (Aβ) in the form of extracellular amyloid plaques in the human brain and (2) tau hyperphosphorylation. Recent publications have implicated the PI3K/mTOR signalling pathway in the pathogenesis of the disease. For example, genetic knock-out of mTOR protein in Tg2576 mice, a widely used animal model of AD, was found to suppress amyloid-β deposits and rescue memory deficits in the animals (J. Neurosci. 2014 Jun. 4; 34(23):7988-98). Furthermore, testing of post-mortem brain tissue from human AD patients highlighted that alteration of mTOR signalling and autophagy occurs at early stages of AD, leading to a significant increase of Aβ (1-42) levels and hyper-activation of the PI3K/Akt/mTOR pathway (J. Neurochem. 2015 Jan. 27). The expression level of S6K1, the mTOR downstream target, was increased in these samples suggesting that a therapeutic intervention by an S6K1 inhibitor may be of utility to control synthesis of amyloid β protein and to dampen signalling from mTOR. Furthermore, increased levels of phosphorylated mTOR and S6K1 were also found in some of the brain areas affected in AD, such as cortex, of double APP/PS1 transgenic mice, a model of AD (Lafay-Chebassier et al., 2005).
In addition, Oddo et al (Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease, The Journal of Neuroscience, Oct. 14, 2015, 35(41):14042-14056) published data that supports the following conclusions: (1) S6K1 activity is upregulated in the brains of AD patients (2) in a mouse model of AD, S6K1 activity in brain is also higher than control (3) Genetic reduction of S6K1 in the AD model mouse (via haplodeficiency) (1) improved synaptic plasticity and spatial memory deficits, and (2) reduced accumulation of Amyloid-B (AB) and phospho-tau/total tau levels, the key neuropathological hallmarks of AD. This validation gives credence to the hypothesis that manipulation of S6K1 activity via a small molecule S6K1 inhibitor could be a valid therapeutic approach in AD.
Huntington's Disease
Huntington's disease is an inherited, progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition); there are two forms of the disease: (1) adult-onset Huntington's disease, the most common form of this disorder, which usually appears in a person's thirties or forties and (2) Juvenile-onset Huntington's disease, which is less common and begins in childhood or adolescence. In both forms the disease is progressive with affected individuals usually living for only 10 to 15 years after signs and symptoms appear. Huntington's disease affects an estimated 3 to 7 people per 100,000 of European ancestry.
Huntington's disease is caused by mutations in the HTT gene which leads to production of an abnormally long version of the huntingtin (Htt) protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington's disease. Recent publications have shown that mutant Htt contributes to the pathogenesis of HD by enhancing mTORC1 activity (Sci. Signal., 28 Oct. 2014, Vol. 7, Issue 349, p. ra103).
One of the functional effectors of mTOR signalling is S6K1; therefore, inhibiting S6K1 function may have ameliorative effects in the disease. In addition, inhibiting S6K1 may limit the production of huntingtin protein via dampening of global protein translation.
Parkinson's Disease
Parkinson's disease (PD) is a progressive neurodegenerative condition resulting from the death of the dopamine-containing cells of the substantia nigra. People with PD classically present with the symptoms and signs associated with parkinsonism, namely bradykinesia, rigidity and rest tremor. PD is a common, chronic, progressive neurological condition, estimated to affect 100-180 people per 100,000 of the population (between 6 and 11 people per 6000 of the general population in the UK) and has an annual incidence of 4-20 per 100,000. There is a rising prevalence with age and a higher prevalence and incidence of PD in males (https://www.nice.org.uk/guidance/cg035/chapter/introduction).
Whilst PD traditionally has been considered a non-genetic disorder, at least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes. Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2 (Lesage S, Brice A; Brice (April 2009). “Parkinson's disease: from monogenic forms to genetic susceptibility factors”. Hum. Mol. Genet. 18 (R1): R48-59).
Recent studies addressing the mechanism of neurodegeneration in PD demonstrate the involvement of the mTORC1 signalling pathway in the survival mechanism of dopaminergic neurons. In vivo and in vitro studies show that degeneration induced by treatment with PD toxins, such as 6-OHDA and MPTP, leads to upregulation of RTP801, a protein encoded by a RTP801 stress-responsive gene, which in turn reduces mTOR kinase activity. It has been proposed that the molecular mechanism, linking high levels of RTP801 to mTORC1 inhibition and neurodegeneration involves TSC2 and Akt (Deyoung et al., 2008; Malagelada et al., 2008). Genetic manipulations that interfere with TSC2 or increase the expression of a constitutively active form of Akt protected against the PD toxins and prevented the increase in RTP801 (Malagelada et al., 2008). However, rapamycin was reported as a neuroprotective agent both in cell culture and in a MPTP mouse model (mouse model of PD). It was proposed that rapamycin may enhance Akt activity through inhibition of mTORC1-dependent activation of S6K1 and the subsequent reduction of phospho-IRS-1, which is a scaffold protein involved in the activation of PI3K and Akt (Shah et al., 2004). It therefore may also be the case that an inhibitor of S6K1 (a main effector of mTOR) will uncouple the same negative feedback loop to IRS-1, leading to activation of Akt and increased survival in the neurons of PD patients. An S6K1 inhibitor may therefore exhibit therapeutic effects when dosed to a PD patient.
For treatment of all the above described diseases it would be advantageous to use an orally bioavailable P70S6K inhibitor with properties allowing penetration of the brain in sufficient concentration to achieve efficacy.
It would therefore be beneficial to develop compounds that have the ability to inhibit p70S6 kinase.
The Invention
The present invention provides a class of novel arylalkylamino-substituted quinazolines as inhibitors of p70S6 kinase.
In a first embodiment (Embodiment 1.0) of the invention, there is provided a compound of the formula (1):
or a salt, tautomer or N-oxide thereof;wherein:                one of Y and Z is R3 and the other is Ar2;        Q1 is a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; and wherein a carbon atom of the C1-8 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 8;        Q2 is a bond or a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;        R1 is selected from hydrogen, NRxRy and a group Cy1;        Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or hydroxy-C1-4 hydrocarbyl; or NRxRy forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NRxRy group;        Cy1 is a C-linked 3 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and oxidised forms of S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy;        R2 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;        R3 is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;        Ar1 is a monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from halogen, cyano and a group Ra—Rb;Ra is a bond, O, CO, X3C(X4), C(X4)X3, X3C(X4)X3, S, SO, SO2, NRc, SO2NRc or NRcSO2;Rb is:        hydrogen;        a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2, NRc, X3C(X4), C(X4)X3 or X3C(X4)X3;R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group;X3 is O, S or NRc; andX4 is ═O, ═S or ═NRc; andRc is hydrogen or C1-4 hydrocarbyl;        Ar2 is a bicyclic 8 to 11-membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S and being optionally substituted with 1, 2 or 3 substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; N(Rc)2; Rc—C(O)—; Rc—C(O)N(Rc)—; (Rc)2NC(O)—; R—SO2NRc—; Rc—NHC(O)NH—; (Rc)2NSO2—; and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R8 selected from C1-4 hydrocarbyl, C1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C1-4 hydrocarbylamino and di-C1-4hydrocarbylamino and wherein the hydrocarbyl moieties when present are optionally substituted with fluorine, C1-2 alkoxy, hydroxy, amino, mono-di-C1-2alkylamino or di-C1-4alkylamino;        and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.        
In another embodiment (Embodiment 1.1) of the invention, there is provided a compound of the formula (1):
or a salt, tautomer or N-oxide thereof;wherein:                one of Y and Z is R3 and the other is Ar2;        Q1 is a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;        Q2 is a bond or a C1-8 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached;        R1 is selected from hydrogen, NRxRy and a group Cy1;        Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or hydroxy-C1-4 hydrocarbyl; or NRxRy forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NRxRy group;        Cy1 is a C-linked 3 to 7 membered monocyclic non-aromatic carbocyclic or heterocyclic group containing 0, 1 or 2 heteroatom ring members selected from N, O and S and oxidised forms of S, wherein the carbocyclic and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy;        R2 and R4 are the same or different and each is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;        R3 is selected from hydrogen, fluorine, chlorine, C1-2 alkyl and C1-2 alkoxy, wherein each C1-2 alkyl and C1-2 alkoxy is optionally substituted with two or more fluorine atoms;        Ar1 is a monocyclic 5 or 6-membered aryl or heteroaryl ring containing 0, 1 or 2 heteroatom ring members selected from O, N and S, the aryl or heteroaryl being optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from halogen, cyano and a group Ra-Rb;Ra is a bond, O, CO, X3C(X4), C(X4)X3, X3C(X4)X3, S, SO, SO2, NRc, SO2NRc or NRcSO2;Rb is:        hydrogen;        a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2, NRc, X3C(X4), C(X4)X3 or X3C(X4)X3;R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group;X3 is O, S or NRc; andX4 is ═O, ═S or ═NRc; andRc is hydrogen or C1-4 hydrocarbyl;        Ar2 is a bicyclic 8 to 11-membered heteroaryl group containing 1, 2, 3 or 4 heteroatom ring members selected from O, N and S and being optionally substituted with 1, 2 or 3 substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; N(Rc)2; Rc—C(O)—; Rc—C(O)N(Rc)—; (Rc)2NC(O)—; R—SO2NRc—; Rc—NHC(O)NH—; (Rc)2NSO2—; and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R8 selected from C1-4 hydrocarbyl, C1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C1-4 hydrocarbylamino and di-C1-4hydrocarbylamino and wherein the hydrocarbyl moieties when present are optionally substituted with fluorine, C1-2 alkoxy, hydroxy, amino, mono-di-C1-2alkylamino or di-C1-4alkylamino;        and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.        
Particular and preferred compounds of the formula (1) are as defined in the Embodiments 1.2 to 1.92 below.
1.2 A compound according to Embodiment 1.0 or 1.1 wherein Y is Ar2 and Z is R3.
1.3 A compound according to Embodiment 1.0 or 1.1 wherein Y is R3 and Z is Ar2.
1.4 A compound according to Embodiment 1.0 or 1.1 having the formula (2):
or a salt, tautomer or N-oxide thereof;wherein R1, R2, R3, R4, Ar1, Ar2, Q1 and Q2 are all as defined in Embodiment 1.0 or 1.1.
1.4A A compound according to Embodiment 1.0 wherein Q1 is a C1-6 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; and wherein a carbon atom of the C1-6 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 6.
1.4B A compound according to Embodiment 1.4A wherein Q1 is a C1-5 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; and wherein a carbon atom of the C1-5 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 5.
1.4C A compound according to Embodiment 1.4B wherein Q1 is a C1-4 alkylene group optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached; and wherein a carbon atom of the C1-4 alkylene group may optionally be replaced by a cyclopropane-1,1-diyl or cyclobutane-1,1-diyl group provided that the total number of carbon atoms in an alkylene group containing such a replacement does not exceed 4.
1.4D A compound according to Embodiment 1.4C wherein Q1 is cyclopropane-1,1-diyl.
1.4E A compound according to Embodiment 1.4C wherein Q1 is cyclobutane-1,1-diyl.
1.5 A compound according to any one of Embodiments 1.0 to 1.4 wherein Q1 is C1-6 alkylene optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached.
1.6 A compound according to Embodiment 1.5 wherein Q1 is C1-4 alkylene optionally substituted by one or two substituents selected from hydroxy and C1-4 hydrocarbyloxy, provided that when a hydroxy substituent is present, there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached.
1.7 A compound according to Embodiment 1.6 wherein the C1-4 alkylene is optionally substituted by one hydroxy substituent, provided that there are at least two carbon atoms between the hydroxy substituent and the nitrogen atom to which Q2 is attached.
1.8 A compound according to any one of Embodiments 1.0 to 1.4 wherein Q1 is a group of the formula —(CRfRg)p— wherein p is 1 to 8, each Rf is independently selected from hydrogen and methyl, and each Rg is independently selected from hydrogen, C1-4 alkyl and hydroxyl-C1-4alkyl, provided that no more than one RG may be larger than methyl and provided that the total number of carbon atoms in —(CRfRg)p— does not exceed 8.
1.9 A compound according to Embodiment 1.8 wherein the total number of carbon atoms in —(CRfRg)p— is in the range 1 to 6.
1.10 A compound according to Embodiment 1.9 wherein the total number of carbon atoms in —(CRfRg)p— is in the range 1 to 4.
1.11 A compound according to any one of Embodiments 1.8 to 1.10 wherein p is 1 or 2.
1.12 A compound according to Embodiment 1.11 wherein p is 1.
1.13 A compound according to any one of Embodiments 1.8 to 1.12 wherein Rf is hydrogen and Rg is selected from hydrogen, methyl, ethyl, isopropyl and hydroxymethyl.
1.13A A compound according to any one of Embodiments 1.8 to 1.12 wherein Rf is hydrogen and Rg is selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl and hydroxyethyl.
1.14 A compound according to Embodiment 1.13 wherein Q1 is selected from CH2, CH(CH3) and CH(CH2OH).
1.14A A compound according to Embodiment 1.13A wherein Q1 is selected from CH2, CH(CH3), CH(CH2OH) and CH(CH2CH2OH).
1.15 A compound according to Embodiment 1.13 wherein Q1 is CH(CH3).
1.16 A compound according to any one of Embodiments 1.0 to 1.4 wherein the moiety —N(Q2-R1)-Q1-Ar1 has the formula:
wherein R9 is hydrogen or a C1-4 alkyl optionally substituted with hydroxyl.
1.17 A compound according to any one of Embodiments 1.0 to 1.4 wherein the moiety -(Q2-R1)N-Q1-Ar1 has the formula:
wherein R9 is hydrogen or a C1-4 alkyl optionally substituted with hydroxyl.
1.18 A compound according to Embodiment 1.16 or 1.17 wherein R9 is hydrogen, methyl, ethyl, isopropyl or hydroxymethyl.
1.18A A compound according to Embodiment 1.16 or 1.17 wherein R9 is hydrogen, methyl, ethyl, isopropyl, hydroxymethyl or hydroxyethyl.
1.19 A compound according to Embodiment 1.18 wherein R9 is hydrogen, methyl or hydroxymethyl.
1.19A A compound according to Embodiment 1.18A wherein R9 is hydrogen, methyl, hydroxymethyl or hydroxyethyl.
1.20 A compound according to Embodiment 1.18 wherein R9 is hydrogen.
1.21 A compound according to Embodiment 1.18 wherein R9 is methyl.
1.22 A compound according to Embodiment 1.18 wherein R9 is hydroxymethyl.
1.22A A compound according to Embodiment 1.18 wherein R9 is hydroxyethyl.
1.23 A compound according to any one of Embodiments 1.0 to 1.22 wherein Q2 is a bond or C1-6 alkylene.
1.24 A compound according to Embodiment 1.23 wherein Q2 is a bond or C1-3 alkylene.
1.25 A compound according to Embodiment 1.24 wherein Q2 is selected from a bond, CH2, CH2CH2 and CH2CH2CH2.
1.26 A compound according to Embodiment 1.25 wherein Q2 is a bond, CH2, or CH2CH2.
1.27 A compound according to Embodiment 1.26 wherein Q2 is a bond.
1.28 A compound according to Embodiment 1.26 wherein Q2 is CH2.
1.29 A compound according to any one of Embodiments 1.0 to 1.28 wherein R1 is selected from hydrogen and a group Cy1.
1.30 A compound according to Embodiment 1.29 wherein R1 is hydrogen.
1.31 A compound according to Embodiment 1.29 wherein R1 is a group Cy1.
1.32 A compound according to any one of Embodiments 1.0 to 1.29 and 1.31 wherein Cy1 is selected from C3-7 cycloalkyl and C-linked 4 to 7 membered non-aromatic heterocyclic groups containing 1 or 2 heteroatom ring members selected from N, O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.
1.33 A compound according to Embodiment 1.32 wherein Cy1 is selected from C3-6 cycloalkyl and C-linked 4 to 6 membered non-aromatic heterocyclic groups containing 1 or 2 heteroatom ring members selected from O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.
1.34 A compound according to Embodiment 1.33 wherein Cy1 is selected from C3-6 cycloalkyl and C-linked 4 to 6 membered saturated non-aromatic heterocyclic groups containing 1 heteroatom ring member selected from O and S, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from saturated C1-3 hydrocarbyl, fluorine, oxo and hydroxy.
1.35 A compound according to Embodiment 1.33 wherein Cy1 is selected from C3-6 cycloalkyl and C-linked 4 to 6 membered saturated non-aromatic heterocyclic groups containing 1 heteroatom ring member selected from O, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine, oxo and hydroxy.
1.36 A compound according to Embodiment 1.33 wherein Cy1 is selected from C3-6 cycloalkyl and C-linked 4 to 6 membered saturated non-aromatic heterocyclic groups containing 1 heteroatom ring member selected from O, wherein the cycloalkyl and heterocyclic groups are unsubstituted or substituted with one or two substituents selected from methyl, fluorine, oxo and hydroxy.
1.37 A compound according to Embodiment 1.33 wherein Cy1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran and tetrahydrofuran.
1.38 A compound according to Embodiment 1.33 wherein Cy1 is tetrahydropyran.
1.39 A compound according to Embodiment 1.32 wherein Cy1 is selected from C-linked 4 to 7 membered non-aromatic heterocyclic groups containing a first ring member which is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 hydrocarbyl, fluorine, oxo and hydroxy.
1.40 A compound according to Embodiment 1.39 wherein Cy1 is selected from C-linked 4 to 7 membered saturated heterocyclic groups containing a first ring member which is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from saturated C1-3 hydrocarbyl, fluorine, oxo and hydroxy.
1.41 A compound according to Embodiment 1.40 wherein Cy1 is selected from C-linked 4 to 7 membered saturated heterocyclic groups containing a first ring member which is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, cyclopropyl, fluorine and hydroxy.
1.42 A compound according to Embodiment 1.41 wherein Cy1 is selected from C-linked azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two substituents selected from C1-3 alkyl, cyclopropyl, fluorine and hydroxy.
1.43 A compound according to Embodiment 1.41 wherein Cy1 is C-linked morpholine.
1.44 A compound according to any one of Embodiments 1.0 to 1.28 wherein R1 is NRxRy.
1.45 A compound according to any one of Embodiments 1.0 to 1.28 and 1.44 wherein Rx and Ry are the same or different and each is selected from hydrogen, C1-4 hydrocarbyl or hydroxy-C1-4 hydrocarbyl.
1.46 A compound according to Embodiment 1.45 wherein Rx and Ry are the same or different and each is selected from hydrogen, saturated C1-4 hydrocarbyl or saturated hydroxy-C1-4 hydrocarbyl.
1.47 A compound according to Embodiment 1.46 wherein Rx and Ry are the same or different and each is selected from hydrogen, C1-4 alkyl, cyclopropyl, methylcyclopropyl, cyclopropylmethyl, and hydroxy-C2-4 alkyl.
1.48 A compound according to Embodiment 1.47 wherein Rx and Ry are the same or different and each is selected from hydrogen and C1-4 alkyl.
1.49 A compound according to Embodiment 1.48 wherein Rx and Ry are the same or different and each is selected from hydrogen and C1-3 alkyl.
1.50 A compound according to Embodiment 1.49 wherein NRxRy is selected from amino, methylamino and dimethylamino.
1.51 A compound according to Embodiment 1.49 wherein NRxRy is dimethylamino.
1.52 A compound according to any one of Embodiments 1.0 to 1.28 and 1.44 wherein NRxRy forms a 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S and oxidised forms thereof, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, mono-C1-4 hydrocarbylamino, di-C1-4hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NRxRy group.
1.53 A compound according to Embodiment 1.52 wherein NRxRy forms a 4 to 7-membered non-aromatic heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 hydrocarbyl, oxo, amino, saturated mono-C1-4 hydrocarbylamino, saturated di-C1-4 hydrocarbylamino, fluorine and hydroxy, provided that there are at least two carbon atoms in line between the amino, saturated mono-C1-4 hydrocarbylamino, saturated di-C1-4 hydrocarbylamino and hydroxy substituents when present and the nitrogen atom of the NRxRy group.
1.54 A compound according to Embodiment 1.53 wherein NRxRy forms a saturated 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-4 alkyl, fluorine, oxo, amino, mono-C1-4 alkylamino, di-C1-4alkylamino and hydroxy.
1.55 A compound according to Embodiment 1.54 wherein NRxRy forms a saturated 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine oxo, amino, mono-C1-2 alkylamino, di-C1-2alkylamino and hydroxy.
1.56 A compound according to Embodiment 1.55 wherein NRxRy forms a saturated 4 to 7-membered heterocyclic ring containing a total of 1 or 2 heteroatom ring members of which one is N and the other is selected from N, O and S, the heterocyclic ring being optionally substituted with one or two substituents selected from methyl, fluorine, oxo, amino, methylamino, dimethylamino and hydroxy.
1.57 A compound according to Embodiment 1.55 wherein NRxRy forms a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine and hydroxy.
1.57 A compound according to Embodiment 1.55 wherein NRxRy forms a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, homomorpholine and thiomorpholine, each being optionally substituted with one or two substituents selected from C1-3 alkyl, fluorine and hydroxy.
1.57A A compound according to any one of Embodiments 1.0 to 1.28 wherein R1 is selected from:                hydrogen;        a group Cy1 wherein Cy1 is selected from 4 to 7 membered saturated heterocyclic groups containing a first ring member which is nitrogen and optionally a second ring member selected from N, O and S, wherein the heterocyclic groups are optionally substituted with one or two substituents selected from C1-3 alkyl, cyclopropyl, fluorine and hydroxyl; and        NRxRy, wherein Rx and Ry are the same or different and each is selected from hydrogen, C1-4 alkyl, cyclopropyl, methylcyclopropyl, cyclopropylmethyl, and hydroxy-C2-4 alkyl.        
1.58 A compound according to any one of Embodiments 1.0 to 1.57A wherein R2 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
1.59 A compound according to Embodiment 1.58 wherein R2 is hydrogen.
1.60 A compound according to any one of Embodiments 1.0 to 1.59 wherein R3 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
1.61 A compound according to Embodiment 1.60 wherein R3 is hydrogen.
1.62 A compound according to any one of Embodiments 1.0 to 1.61 wherein R4 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
1.63 A compound according to Embodiment 1.62 wherein R4 is hydrogen.
1.64 A compound according to any one of Embodiments 1.0 to 1.63 wherein Ar1 is a monocyclic aryl or heteroaryl ring selected from phenyl, furyl, thienyl, pyridyl and pyrimidinyl, each optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are as defined in Embodiment 1.1.
1.65 A compound according to Embodiment 1.64 wherein Ar1 is a monocyclic aryl or heteroaryl ring selected from phenyl, furyl, thienyl and pyridyl, each optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are as defined in Embodiment 1.1.
1.66 A compound according to Embodiment 1.65 wherein Ar1 is a phenyl ring optionally substituted with 1, 2 or 3 substituents R5 which are the same or different and are as defined in Embodiment 1.1.
1.67 A compound according to any one of Embodiments 1.0 to 1.66 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from fluorine, chlorine, bromine, cyano and a group Ra—Rb;
Ra is a bond, O, CO, NRcC(═O), C(═O)NRc, NRcC(═O)NR, C(═O) O, OC(═O), S, SO, SO2, NRc, SO2NRc or NRcSO2;
Rb is:
                hydrogen;        a carbocyclic or heterocyclic group having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; amino; mono- or di-C1-4 alkylamino; and carbocyclic and heterocyclic groups having from 3 to 7 ring members, of which 0, 1, 2 or 3 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NRc;R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group; andRc is hydrogen or C1-4 hydrocarbyl.        
1.68 A compound according to Embodiment 1.67 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from fluorine, chlorine, bromine, cyano and a group Ra—Rb;
Ra is a bond, O, CO, NRcC(═O), C(═O)NRc, NRcC(═O)NR, C(═O) O, OC(═O), S, SO, SO2, NRc, SO2NRc or NRcSO2;
Rb is:
                hydrogen;        a non-aromatic carbocyclic or heterocyclic group having from 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N, S and SO2, the non-aromatic carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; and        an acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; halogen; cyano; amino; mono- or di-C1-4 alkylamino; and non-aromatic carbocyclic and heterocyclic groups having from 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N, S and SO2, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O, S, SO, SO2 or NRc;R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group; andRc is hydrogen or C1-4 hydrocarbyl.        
1.69 A compound according to Embodiment 1.68 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 which are the same or different and are selected from fluorine, chlorine, bromine, cyano and a group Ra—Rb;
Ra is a bond, O, CO, NRcC(═O), C(═O)NRc, SO2, NRc, SO2NRc or NRcSO2;
Rb is:
                hydrogen;        a non-aromatic carbocyclic or heterocyclic group having from 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S, the non-aromatic carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; and        a saturated acyclic C1-8 hydrocarbon group optionally substituted with one or more substituents selected from hydroxy; oxo; fluorine; cyano; amino; mono- or di-C1-2 alkylamino; and non-aromatic carbocyclic and heterocyclic groups having from 3 to 6 ring members, of which 0, 1 or 2 are heteroatom ring members selected from O, N and S and oxidised forms of S, the carbocyclic or heterocyclic group being optionally substituted with one or more substituents R6; wherein one or two but not all of the carbon atoms of the acyclic C1-8 hydrocarbon group may optionally be replaced by O or NRc;R6 is selected from the substituents R5 except that R6 does not consist of or contain a carbocyclic or heterocyclic group; andRc is hydrogen, C1-4 alkyl, cyclopropyl or cyclopropylmethyl.        
1.70 A compound according to any one of Embodiments 1.0 to 1.66 wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-3 alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen or C1-3 alkyl; R11 is hydrogen or C1-3 alkyl; R12 is hydrogen or C1-3 alkyl; k is 2, 3 or 4; m is 0 or 1; and n is 1, 2, 3 or 4 provided that when m is 1 then n is 2, 3 or 4; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0, 1, 2 or 3 provided that the total of p and q does not exceed 4; and Cy2 is a non-aromatic carbocyclic or heterocyclic ring of three to seven ring members, containing 0, 1 or 2 heteroatom ring members selected from O, N and S and being optionally substituted by one, two or three substituents selected from hydroxy, C1-4 hydrocarbyl, C1-4 hydrocarbyl-C(═O), oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4 hydrocarbylamino and fluorine.
1.70A A compound according to any one of Embodiments 1.0 to 1.66 wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-3 alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkylsulphonylamino; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen or C1-3 alkyl; R11 is hydrogen or C1-3 alkyl; R12 is hydrogen or C1-3 alkyl; k is 2, 3 or 4; m is 0 or 1; and n is 1, 2, 3 or 4 provided that when m is 1 then n is 2, 3 or 4; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0, 1, 2 or 3 provided that the total of p and q does not exceed 4; and Cy2 is a non-aromatic carbocyclic or heterocyclic ring of three to seven ring members, containing 0, 1 or 2 heteroatom ring members selected from O, N and S and being optionally substituted by one, two or three substituents selected from hydroxy, C1-4 hydrocarbyl, C1-4 hydrocarbyl-C(═O), oxo, amino, mono-C1-4 hydrocarbylamino, di-C1-4 hydrocarbylamino and fluorine.
1.71 A compound according to Embodiment 1.70 wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-3 alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3 provided that when m is 1 then n is 2 or 3; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0, 1 or 2; and Cy2 is a non-aromatic carbocyclic ring of three to six ring members or a heterocyclic ring of five or six ring members, containing 1 or 2 heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings each being optionally substituted by one, two or three substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.
1.71A A compound according to Embodiment 1.70A wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-3 alkylamino; di-C1-3 alkylamino; C1-3 alkanoyl; C1-3 alkylsulphonylamino; C1-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3 provided that when m is 1 then n is 2 or 3; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0, 1 or 2; and Cy2 is a non-aromatic carbocyclic ring of three to six ring members or a heterocyclic ring of five or six ring members, containing 1 or 2 heteroatom ring members selected from O, N and S, the carbocyclic and heterocyclic rings each being optionally substituted by one, two or three substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.
1.72 A compound according to Embodiment 1.71 wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-2 alkylamino; di-C1-2 alkylamino; C1-3 alkanoyl; C2-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3 provided that when m is 1 then n is 2 or 3; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0 or 1; and Cy2 is a non-aromatic heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.
1.72A A compound according to Embodiment 1.71A wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-3 alkyl; C1-3 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-2 alkylamino; di-C1-2 alkylamino; C1-3 alkanoyl; C1-2 alkylsulphonylamino; C2-3 alkanoylamino; carbamoyl; mono-C1-3 alkyl carbamoyl; di-C1-3 alkyl carbamoyl; a group O—(CH2)k—OR10; and a group Om—(CH2)n—NR11R12; R10 is hydrogen, methyl or ethyl; R11 is hydrogen, methyl or ethyl; R12 is hydrogen, methyl; or ethyl; k is 2 or 3; m is 0 or 1; and n is 1, 2 or 3 provided that when m is 1 then n is 2 or 3; L1 is a bond or a linker group selected from C1-4 alkylene, —(CH2)p—NH—(CH2)q—, —(CH2)p—N(CH3)—(CH2)q—, —(CH2)p—C(═O)—(CH2)q—, —(CH2)p—C(═O)NH—(CH2)q—, —(CH2)p—C(═O)N(CH3)—(CH2)q—, —(CH2)p—NHC(═O)—(CH2)q— and —(CH2)p—N(CH3)C(═O)—(CH2)q—; p and q are each independently 0 or 1; and Cy2 is a non-aromatic heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, C1-4 alkyl, cyclopropyl, cyclopropylmethyl, C1-4 alkanoyl, cyclopropylcarbonyl, oxo and fluorine.
1.73 A compound according to Embodiment 1.72 wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-2 alkyl; C1-2 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; amino; mono-C1-2 alkylamino; di-C1-2 alkylamino; acetyl; acetylamino; carbamoyl; mono-C1-2 alkyl carbamoyl; di-C1-2 alkyl carbamoyl; dimethylaminoethoxy; wherein L1 is selected from a bond, O, NH, N(CH3), NHC(═O), C(═O)NH, N(CH3)C(═O) and C(═O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, methyl and oxo.
1.73A A compound according to Embodiment 1.72A wherein Ar1 is unsubstituted or is substituted with 1, 2 or 3 substituents R5 selected from a group L1-Cy2; fluorine; chlorine; bromine; C1-2 alkyl; C1-2 alkoxy; trifluoromethyl; difluoromethyl; hydroxy; cyano; trifluoromethoxy; difluoromethoxy; C1-2 alkylsulphonylamino; amino; mono-C1-2 alkylamino; di-C1-2 alkylamino; acetyl; acetylamino; carbamoyl; mono-C1-2 alkyl carbamoyl; di-C1-2 alkyl carbamoyl; dimethylaminoethoxy; wherein L1 is selected from a bond, O, NH, N(CH3), NHC(═O), C(═O)NH, N(CH3)C(═O) and C(═O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from hydroxy, methyl and oxo.
1.74 A compound according to Embodiment 1.73 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, bromine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy, difluoromethoxy, morpholinyl, piperazinyl, N-methylpiperazinyl and dimethylaminoethoxy.
1.74A A compound according to Embodiment 1.73A wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, bromine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy, difluoromethoxy, methylsulphonylamino, morpholinyl, piperazinyl, N-methylpiperazinyl and dimethylaminoethoxy.
1.75 A compound according to any one of Embodiments 1.0 to 1.66 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from L1-Cy2; fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy and dimethylaminoethoxy; wherein L1 is selected from a bond, 0, NH, NHC(═O), C(═O)NH and C(═O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from methyl and oxo.
1.75A A compound according to any one of Embodiments 1.0 to 1.66 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from L1-Cy2; fluorine, chlorine, methyl, hydroxy, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, methylsulphonylamino and dimethylaminoethoxy; wherein L1 is selected from a bond, 0, NH, NHC(═O), C(═O)NH and C(═O)N(CH3); and Cy2 is selected from piperidine, piperazine, morpholine and tetrahydropyran, the heterocyclic ring being optionally substituted by one or two substituents selected from methyl and oxo.
1.76 A compound according to Embodiment 1.75 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy and difluoromethoxy.
1.76A A compound according to Embodiment 1.75A wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, methylsulphonylamino, trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy and difluoromethoxy.
1.77 A compound according to Embodiment 1.76 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.
1.77A A compound according to Embodiment 1.76A wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, methyl, hydroxyl, methoxy, methylsulphonylamino, trifluoromethyl and trifluoromethoxy.
1.78 A compound according to Embodiment 1.77 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, methyl and methoxy.
1.78A A compound according to Embodiment 1.77A wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine, methylsulphonylamino, methyl and methoxy.
1.79 A compound according to Embodiment 1.78 wherein Ar1 is unsubstituted or substituted with 1, 2 or 3 substituents R5 selected from fluorine, chlorine and methoxy.
1.80 A compound according to any one of Embodiments 1.0 to 1.79 wherein Ar1 is unsubstituted or substituted with one or two substituents R5.
1.81 A compound according to Embodiment 1.80 wherein Ar1 is unsubstituted or substituted with one substituent R5.
1.82 A compound according to Embodiment 1.81 wherein Ar1 is unsubstituted.
1.83 A compound according to Embodiment 1.81 wherein Ar1 is substituted with one substituent R5.
1.84 A compound according to Embodiment 1.80 wherein Ar1 is a phenyl ring which is unsubstituted or is substituted with one or two substituents R5 wherein at least one substituent R5 is present at the meta- or para-position of the phenyl ring.
1.85 A compound according to Embodiment 1.84 wherein Ar1 is a phenyl ring which is substituted with one substituent R5 which is present at the meta-position of the phenyl ring.
1.86 A compound according to Embodiment 1.84 wherein Ar1 is a phenyl ring which is substituted with one substituent R5 which is present at the para-position of the phenyl ring.
1.87 A compound according to Embodiment 1.84 wherein Ar1 is a phenyl ring which is unsubstituted or is substituted with one substituent R5 selected from 3-chloro, 4-chloro, 3-fluoro, 4-fluoro, 3-methoxy, 4-methoxy, 3-methyl and 4-methyl.
1.88 A compound according to Embodiment 1.87 wherein Ar1 is a phenyl ring which is unsubstituted or is substituted with one substituent R5 selected from 3-chloro, 3-fluoro, 4-fluoro and 3-methoxy.
1.89 A compound according to Embodiment 1.84 wherein Ar1 is a phenyl ring which is substituted with two substituents R5.
1.90 A compound according to Embodiment 1.89 wherein Ar1 is a phenyl ring which is substituted with two substituents R5, wherein one substituent is present at the para-position of the phenyl ring and the other is present at the meta-substituent of the phenyl ring.
1.91 A compound according to Embodiment 1.90 wherein Ar1 is 3,4-difluorophenyl.
1.91A A compound according to Embodiment 1.82 wherein Ar1 is unsubstituted phenyl.
1.91B A compound according to Embodiment 1.66 wherein Ar1 is unsubstituted phenyl or phenyl substituted with one or two substituents selected from fluorine, chlorine, methoxy, methylsulphonylamino and hydroxyl.
1.91C A compound according to Embodiment 1.66 wherein Ar1 is unsubstituted phenyl or phenyl substituted with one or two substituents selected from fluorine, chlorine, methoxy and methylsulphonylamino.
1.91D A compound according to Embodiment 1.66 wherein Ar1 is selected from unsubstituted phenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3-methoxyphenyl, 3-methylsulphonylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl.
1.91E A compound according to Embodiment 1.66 wherein Ar1 is selected from unsubstituted phenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3-methoxyphenyl, 3-methylsulphonylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl
1.92 A compound according to any one of Embodiments 1.0 to 1.91 wherein Ar2 is selected from 5.6 fused heteroaromatic rings and 6.6 fused heteroaromatic rings, each containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S and being optionally substituted by 1, 2, or 3 substituents R7 as defined in Embodiment 1.1.
1.93 A compound according to Embodiment 1.92 wherein the 5.6 fused heteroaromatic rings and 6.6 fused heteroaromatic rings each contain 1, 2, 3 or 4 nitrogen heteroatom ring members.
1.94 A compound according to Embodiment 1.92 or 1.93 wherein Ar2 is selected from 5.6 fused heteroaromatic rings, each being optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.
1.95 A compound according to Embodiment 1.94 wherein Ar2 is selected from pyrimido-imidazole, pyrido-imidazole, pyrimido-pyrrole, pyrido-pyrrole, benzo-imidazole, benzo-pyrrole, pyrimido-pyrazole, pyrido-pyrazole and benzo-pyrazole groups, each being optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.
1.95A A compound according to Embodiment 1.95 wherein Ar2 is selected from pyrimido-pyrrole, pyrido-pyrrole, pyrimido-pyrazole, pyrido-pyrazole groups and pyrimido-imidazole groups, each optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.
1.96 A compound according to Embodiment 1.95 wherein Ar2 is selected from pyrimido-pyrrole, pyrido-pyrrole, pyrimido-pyrazole and pyrido-pyrazole groups, each optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.
1.97 A compound according to Embodiment 1.96 wherein Ar2 is a pyrimido-pyrazole group, which is optionally substituted by 1, 2 or 3 substituents R7 as defined in Embodiment 1.1.
1.98 A compound as defined in any one of Embodiments 1.0 to 1.97 wherein Ar2 is unsubstituted or is substituted with one or two substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 hydrocarbyl optionally substituted with one or more fluorine atoms; C1-4 hydrocarbyloxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; and five and six-membered monocyclic groups containing from 0 to 3 heteroatom ring members selected from O, N and S, the five and six-membered monocyclic groups being unsubstituted or substituted with one or more substituents R8 selected from C1-4 hydrocarbyl, C1-4 hydrocarbyloxy, cyano, hydroxy, oxo, halogen, amino, mono-C1-4 hydrocarbylamino and di-C1-4hydrocarbylamino.
1.99 A compound as defined in Embodiment 1.98 wherein Ar2 is unsubstituted or is substituted with one or two substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy; cyano; and five and six-membered monocyclic groups selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrole, pyrazole, imidazole, thiophene, furan, oxazole and isoxazole, the five and six-membered monocyclic groups each being unsubstituted or substituted with one or more substituents R8 selected from C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, fluorine, chlorine, amino, methylamino and dimethylamino.
1.100 A compound as defined in Embodiment 1.99 wherein Ar2 is unsubstituted or is substituted with one or two substituents R7 selected from oxo, fluorine; chlorine; bromine; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy and cyano.
1.101 A compound as defined in Embodiment 1.100 wherein Ar2 is unsubstituted or is substituted with one or two substituents R7 selected from oxo, methyl, difluoromethyl, trifluoromethyl, amino, hydroxy and cyano.
1.102 A compound as defined in any one of Embodiments 1.0 to 1.101 wherein Ar2 is unsubstituted or is mono-substituted.
1.103 A compound as defined in Embodiment 1.102 wherein Ar2 is unsubstituted or is mono-substituted with one substituent R7 selected from methyl and amino.
1.103AA compound as defined in Embodiment 1.102 wherein Ar2 is unsubstituted or is mono-substituted with one substituent R7 selected from methyl and cyano.
1.104 A compound as defined in Embodiment 1.103 wherein Ar2 is unsubstituted or is substituted with one substituent R7 which is methyl.
1.105 A compound as defined in Embodiment 1.104 wherein Ar2 is unsubstituted.
1.106 A compound as defined in any one of Embodiments 1.0 to 1.105 wherein Ar2 is:
where * denotes the point of attachment to the quinazoline ring.
1.107 A compound of the formula (3):
or a salt, tautomer or N-oxide thereof, wherein R1, R2, R3, R4, Q1, Q2 and Ar1 are as defined in any one of Embodiments 1.0 to 1.106.
1.108 A compound of the formula (4):
or a salt, tautomer or N-oxide thereof, wherein R1, R2, R3, R4, R5, Q1 and Q2 are as defined in any one of Embodiments 1.0 to 1.106; and x is 0, 1 or 2.
1.109 A compound according to Embodiment 1.108 wherein Q1 is CH2 or CH(CH3), Q2 is a bond or CH2 and R1 is hydrogen.
1.110 A compound according to Embodiment 1.108 or Embodiment 1.109 wherein x is 0 or 1.
1.111 A compound selected from the title compounds of Examples 1 to 43 herein.
1.112 A compound according to any one of Embodiments 1.0 to 1.111 which is in the form of a salt.
1.113 A compound according to Embodiment 1.112 wherein the salt is an acid addition salt.
1.114 A compound according to Embodiment 1.112 or Embodiment 1.113 wherein the salt is a pharmaceutically acceptable salt.
1.115 A compound according to any one of Embodiments 1.0 to 1.114 which is in the form of a solvate.
1.116 A compound according to Embodiment 1.115 wherein the solvate is a hydrate.